1. Field of the Invention
The invention mainly relates to a modified allergen obtained by altering Der p 5 allergen of house dust mite and the pharmaceutical uses thereof.
2. Description of the Related Art
Allergy refers to an acquired potential to develop immunologically mediated adverse reaction to normally innocuous substances. Allergic reaction provokes symptoms such as itching, coughing, wheezing, sneezing, watery eyes, inflammation and fatigue. Many allergic diseases are due to several kinds of symptoms which are developed by sensitization to the antigen causing the diseases. In an allergic disease, an IgE antibody specific for an allergen (e.g. pollens and mite dust) in blood serum and tissue is produced, and when the antibody is exposed again to the antigen, the antibody reacts with the antigen in each tissue. It is normally believed that an allergic reaction includes an early specific immune response and a late inflammatory reaction. It is reported that an allergen mediates the early phase of allergy by stimulating high affinity immunoglobulin (IgE) receptors. Mast cells and basophils, when stimulated by allergens, will release histamine and cytokines. The cytokines released from mast cells and basophils then mediate the late phase of allergy by recruiting inflammatory cells.
It is reported that allergic diseases, such as bronchial asthma, childhood asthma, atopic dermatitis and the like, are mainly caused by allergens from mites living in house dust. Several kinds of proteins of mite allergens, such as Der p 1 and Der p 2, have been identified. Der p 5 is a 14-k Da group 5 mite allergen which contains a 19-residue leader protein and a 113-residue mature protein was cloned and sequenced (Lin et al., Allergens, IgE, mediators, inflammatory mechanisms. J Allergy Clin Immunol 1994; 6:989-996). Although only 60% of mite-allergic children reacted to Der p 5, the IgE reactivity appeared to be stronger than that of Der p 1 and Der p 2 in Taiwan. Furthermore, among the various allergic diseases, the group of children with asthma have significant more reactivity than the group with rhinitis alone. Der p 5 is regarded as a clinically significant allergen in mite allergy.
Various therapies have been pursued in order to treat the symptoms of allergies. Particularly, “oral tolerance” is considered to be an ideal candidate for treatment of an allergic disease. Oral tolerance has been characterized as a state of antigen-specific systemic immunological unresponsiveness or tolerance, which is induced by prior oral administration or feeding of antigen. The primary mechanism by which an orally administered antigen induces tolerance is believed to be via the generation of active suppression or clonal anergy.
However, directly administrating wild-type mite allergens may raise an allergic reaction, namely anaphylactic shock, in hyposensitization therapy, because the activity of these wild-type allergens is high. If the binding between the antigen and the IgE antibody is controlled, the crosslinking among the IgE antibodies on mast cells or basophils, and the release of histamine and cytokines are controlled to treat allergic diseases. Regarding Der p 1 and Der p 2, the B-cell epitopes and T-cell epitopes have been demonstrated, and the side-directed mutagenesis of Der p 1 and Der p 2 in order to inhibit IgE binding when exposed again to the antigen has been disclosed in U.S. Pat. No. 6,187,311, but nothing on Der p 5 has been disclosed.